Transdermal therapeutic systems (TTS) as pharmaceutical administration forms have been known for a long time. For the transdermal administration of active pharmaceutical ingredients by means of TTS, the stratum corneum (SC), the outermost layer of the skin, in the majority of cases constitutes the real barrier for the permeability and for the rate of passage of the active pharmaceutical ingredient.
Peptides and proteins and also other high-molecular molecules, with a molecular weight of more than 500 daltons—such as, for example, tacrolimus, heparin, and numerous salts of betamethasone—are generally not absorbed transdermally, owing to their molecular size and to their physicochemical properties.
Moreover, the majority of peptides possess a low oral bioavailability and are subject to severe, proteolytic degradation in the gastrointestinal tract. For these reasons, peptides are commonly administered parenterally, bypassing the gastrointestinal tract. This involves injections or infusions which are administered below the skin, into the muscle or directly into the bloodstream.
The transdermal route here would offer a noninvasive alternative—with high patient compliance—to this invasive, parenteral administration. Consequently there are numerous approaches to facilitating the permeability of the skin for molecules having a molecular weight of more than 500 daltons. These approaches include, primarily, the use of permeation enhancers or the additional use of heat.
Another technique for making molecules with poor skin transit amenable to transdermal administration is to facilitate the passage of an active ingredient of this kind through the stratum corneum by partly destroying or removing this layer beforehand. These techniques, referred to as “skin ablation”, use thermal or mechanical energy in order to effect partial destruction or removal of the stratum corneum and hence to create direct channels into the living epidermis. The permeability of the skin is increased and the transdermal absorption of high-molecular-weight molecules can therefore be made possible.
As a result of this pretreatment of the skin, moreover, it is also possible for hydrophilic active ingredients to be administered transdermally, the transdermal route having hitherto been closed to such ingredients on account of their hydrophilicity. Ingredients contemplated here include, for example, fentanyl citrate, granisetrone HCl, Na diclofenac, and apomorphine sulfate. Furthermore, the TTS area of existing TTS systems can be reduced significantly, for the same blood levels, by means of skin ablation pretreatment.
The skin ablation technique commonly generates a multiplicity of microchannels through the stratum corneum, and yet the percentage “perforated” proportion of the treated skin area is relatively small. A description of the laser skin ablation technique is present in WO 2007/039646, whose US equivalent is United States Patent Publication No. 2008/255034.A1.
Triptorelin is a peptide hormone having a molecular weight of 1311 Da. It is employed for the treatment of advanced prostate cancer, in endometriosis, and in premature puberty. Another area of application is in in vitro fertilization (assistive fertility therapy). For these purposes, triptorelin is available as a ready-to-inject solution (under the brand name DECAPEPTYL ®, UROPEPTYL DEPOT®), and as a dry substance with solvent for producing a suspension for injection (under the brand name PAMORELIN®). Triptorelin here is used as salt in the form of the diacetate or embonate, respectively. In a triptorelin treatment, the solution, optionally prepared by the patient shortly before administration of the solution, is administered by injection. Triptorelin therapy may last for a period of several weeks to months and may require once-daily injection.
Desmopressin is a synthetic analogue of the peptide hormone vasopressin, having a molecular weight of 1069 Da, and is used as a pharmaceutical (antidiuretic). Desmopressin is an antidiuretic. In addition there is also an indication for enuresis nocturna (bedwetting). Desmopressin can also be given as an antihemorrhagic in cases, for example, of hemophilia, uremic thrombocytopathy or Willebrand-Jürgens syndrome. For these purposes, desmopressin is available in the form of tablets (MINIRIN®), an injection solution (MINIRIN PARENTERAL®) or a nasal spray (MINIRIN®, Desmopressin TAD®).
Vasopressin is a peptide hormone having a molecular weight of 1084 Da. Vasopressin is used as a highly hypertensive substance successfully in patients in a state of shock. Diabetes insipidus centralis (ICD-10: E23.3 and N25.1) can be treated by administration of vasopressin.
The known products, however, possess certain disadvantages, which are attributable in particular to the low stability of the peptides in solution, this low stability being common knowledge.
For instance, the time for which ready-to-inject solution can be kept is only 3 weeks. The greatest disadvantage, however, is the low level of patient compliance with injection, owing to the invasive nature of the treatment. Molecules of high molecular weight have to date been closed off from transdermal administration as a result of their physicochemical properties. Transdermal administration of these molecules is made possible only by pretreatment of the skin.
In order to increase the stability and hence the time for which the peptide preparations can be kept, the injection solution is prepared not until immediately prior to administration, by mixing of the dry active ingredient (usually freeze-dried) with the solvent. The approach of allowing the injection suspension to be prepared by the patient not until shortly before its administration entails the risk of an imprecise dosing. In addition, the dispensing of powders on the industrial scale represents a task which imposes very exacting requirements on accuracy, particularly in the case of such a highly efficient active ingredient as a peptide hormone. In the pharmaceutical industry, therefore, the aim as far as possible is to avoid operating with solids.
Lastly, injection itself may be accompanied by difficulties, which lie primarily in pain during application, a risk of injury, and the risk of infections.